Man is able to conserve protein during prolonged starvation; however, the mechanism by which he accomplishes this is not known. Studies from our laboratory indicate that older and particularly older obese rats are able to conserve tissue protein and RNA during fasts of 10 days or more, whereas young lean rats cannot. We will make use of these differences between rats to study systematically the factors responsible for protein conservation during starvation. It is our hypothesis that protein conservation during prolonged starvation is in some way related to the continued use of lipid fuels, but that other factors may play a more important role in regulating protein catabolism early in starvation. Particular attention will be focused on the relative importance of age and the availability of lipid fuels on the one hand and the levels & biological effectiveness of T3, insulin and corticosterone on the other. Initially, young and old rats, and rats of the same age but with different degrees of adiposity will be longitudinally studied during a fast and their abilities to diminish excretion in the urine of nitrogen, urea and 3-methylhistidine and to conserve RNA and protein in individual organs will be compared. The groups will also be compared with respect to circulating levels of hormones and fuels, the activities of selected proteases, and the redox state of muscle, and protein turnover. The latter will be assessed in skeletal muscle utilizing a perfused hindquarter preparation. On the basis of these studies, we will design experiments to assess tissue sensitivity to insulin, T3, and FFA at key times during a fast. Also, we will evaluate the effect of altering the concentrations of these substances on protein catabolism in early and late starvation and during end-stage starvation when lipid stores are depleted. The experiments should help to elucidate the factors responsible for protein conservation in the fasting rat and by implication in man. In addition, the information obtained from this work should provide a basic frame of reference for future studies of the regulation of nitrogen metabolism in animal models.